scholarly journals Biopsy-induced inflammatory conditions improve endometrial receptivity: the mechanism of action

Reproduction ◽  
2015 ◽  
Vol 149 (1) ◽  
pp. 75-85 ◽  
Author(s):  
Y Gnainsky ◽  
I Granot ◽  
P Aldo ◽  
A Barash ◽  
Y Or ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Endometrial Biopsy ◽  
Implantation Failure ◽  
Uterine Receptivity ◽  
Recurrent Implantation Failure ◽  
Endometrial Stromal Cells ◽  
Inflammatory Conditions ◽  
Adhesive Molecule ◽  
Inflammatory Milieu ◽  
Endometrial Epithelial Cells

A decade ago, we first reported that endometrial biopsy significantly improves the success of pregnancy in IVF patients with recurrent implantation failure, an observation that was later confirmed by others. Recently, we have demonstrated that this treatment elevated the levels of endometrial pro-inflammatory cytokines and increased the abundance of macrophages (Mac) and dendritic cells (DCs). We therefore hypothesised that the biopsy-related successful pregnancy is secondary to an inflammatory response, and aimed at deciphering its mechanism of action. Supporting our hypothesis, we found that the pro-inflammatory TNFα stimulated primary endometrial stromal cells to express cytokines that attracted monocytes and induced their differentiation into DCs. These monocyte-derived DCs stimulated endometrial epithelial cells to express the adhesive moleculeSPP1(osteopontin (OPN)) and its receptorsITGB3andCD44, whereasMUC16, which interferes with adhesion, was downregulated. Other implantation-associated genes, such asCHST2,CCL4(MIP1B) andGROA, were upregulated by monocyte-derived Mac. These findings suggest that uterine receptivity is mediated by the expression of molecules associated with inflammation. Such an inflammatory milieu is not generated in some IVF patients with recurrent implantation failure in the absence of local injury provoked by the biopsy treatment.

scholarly journals Increased expression of HMGB1 in the implantation phase endometrium is related to recurrent implantation failure

2021 ◽  
Author(s):  
Mi Han ◽  
Yi Cao ◽  
Wenjie Zhou ◽  
Mingjuan Zhou ◽  
Xiaowei Zhou ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Underlying Mechanism ◽  
Endometrial Receptivity ◽  
In Vitro Assays ◽  
Control Group ◽  
Implantation Failure ◽  
Recurrent Implantation Failure ◽  
Tubal Infertility ◽  
Endometrial Stromal Cells

Abstract Impaired endometrial receptivity is the main cause of recurrent implantation failure (RIF), however, its underlying mechanism is unclear. In this study, we found that HMGB1 expression was significantly decreased in the implantation phase endometrium in the control group (patients with tubal infertility who successfully achieved conception after the first embryo transfer) (P = 0.006). However, the expression levels of HMGB1 mRNA and protein were significantly upregulated during the implantation phase in endometrial tissues obtained from patients with RIF compared to those in the control group (P = 0.001), consistent with the results of genome-wide expression profiling. Moreover, in vitro assays showed that increased expression of HMGB1 in human endometrial epithelial cells cause marked deficiency in supporting blastocysts and human embryonic JAR cell adhesion, mimicking the process of embryo adhesion. However, overexpression of HMGB1 had no effect on cell proliferation and in-vitro decidualization in a human endometrial stromal cell line (T-HESCs) and in primary human endometrial stromal cells (HESCs). These findings indicate that increased HMGB1 levels suppressed the adhesion capability of epithelial cells, contributing to impaired endometrial receptivity in patients with recurrent implantation failure. This characteristic can be used as a target for detecting and treating recurrent implantation failure in clinical practice.

P–387 Serum progesterone levels on the day of the endometrial receptivity analysis (ERA) biopsy do not correlate with the biopsy results

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
S Ahuja ◽  
A Taranissi ◽  
M Taranissi
Keyword(s):  
Embryo Transfer ◽  
Essential Element ◽  
Endometrial Biopsy ◽  
Endometrial Receptivity ◽  
Implantation Failure ◽  
Recurrent Implantation Failure ◽  
Serum Progesterone ◽  
Endometrial Cells ◽  
Live Births ◽  
Negative Results

Abstract Study question Do the serum progesterone levels on the day of the endometrial receptivity analysis (ERA) biopsy correlate with the results of the ERA? Summary answer Serum progesterone levels on the day of the endometrial receptivity analysis biopsy do not correlate with the biopsy results. What is known already Endometrial receptivity is a time sensitive window characterised by maturation of the endometrium, during which the trophectodermal cells attach to the endometrial cells and invade the endometrial stromal vasculature. Progesterone is an essential element for receptivity and pregnancy. There is no consensus regarding the optimal progesterone levels in the luteal phase, for a successful pregnancy. Endometrial receptivity analysis is a diagnostic tool developed by profiling the transcriptome of over 238 genes that are expressed at different stages of the endometrial cycle. The results are reported as receptive, pre-receptive, early receptive, etc and are used to direct a personalised embryo transfer. Study design, size, duration We report a prospective study of 30 patients with a history of recurrent implantation failure (RIF). They underwent ERA testing in a medicated cycle, between early 2018 and late 2020. Participants/materials, setting, methods A large proportion of the patients we treat in our clinic (ARGC) have recurrent implantation failure. Thirty patients with RIF underwent ERA testing in a medicated cycle.They all followed the same protocol with down regulation, followed by estrogenic preparation for about 12–14 days, followed by progesterone for about 120 hours. An endometrial biopsy was taken at about 120 hours after progesterone exposure. Main results and the role of chance An ERA result was available on 28/30 patients. Eighteen were reported to be pre-receptive, seven receptive, 3 early receptive and 2 could not be analysed. The progesterone levels within 24 hours of the biopsy for the pre-receptive group ranged from 21.2–472 nmol/l, for the receptive group ranged from 27.8–152 nmol/l and for the early receptive group ranged from 54.9–162 nmol/l. Though the number of cases is small, we found no co-relation between the serum progesterone levels with the ERA results. Eighteen women underwent an embryo transfer based on the ERA results (pET-personalised embryo transfer). Eleven were positive with four live births, one early ongoing pregnancy, three miscarriages, one ectopic pregnancy, two biochemical pregnancies and seven negative results. Seven women had euploid embryo transfers-three had live births, one is viable at 11 weeks, one had a missed miscarriage and two were negative. There are no studies correlating the serum progesterone levels and the ERA results. In practice, we plan embryo transfers for women in frozen cycles by monitoring the serum progesterone levels alongside the day of the cycle. Hence, we wanted to review if the combination of the progesterone levels along with biopsy results would allow us the improve the results further. Limitations, reasons for caution This is a small study. Larger datasets are required to draw meaningful conclusions. Wider implications of the findings: If the above findings are confirmed by larger studies, we may not need to monitor serum progesterone levels during ERA biopsy cycles. Trial registration number NA

scholarly journals Endometrial inflammation and effect on implantation improvement and pregnancy outcome

Reproduction ◽  
2012 ◽  
Vol 144 (6) ◽  
pp. 661-668 ◽  
Author(s):  
I Granot ◽  
Y Gnainsky ◽  
N Dekel
Keyword(s):  
Inflammatory Response ◽  
Pregnancy Outcome ◽  
Immune Cells ◽  
Embryo Implantation ◽  
Substantial Improvement ◽  
Subsequent Pregnancy ◽  
Endometrial Biopsy ◽  
Implantation Failure ◽  
Uterine Receptivity ◽  
Major Barrier

Implantation failure, which is presently the major barrier in human fertility, is attributed, in many cases, to the failure of the uterus to acquire receptivity. The transition into a receptive uterus includes cellular changes in the endometrium and the modulated expression of different cytokines, growth factors, transcription factors, and prostaglandins. These molecules partake in the generation of an inflammatory response followed by the recruitment of immune cells. These cells have shown to be involved in the maternal immune tolerance toward the implanted embryo as well as in the maternal–fetus interaction during pregnancy. Most of the accumulated evidence indicates that embryo implantation is associated with an active Th1 inflammatory response while a Th2-humoral inflammation is required for pregnancy maintenance. Yet, recent findings suggest that a Th1 inflammatory response is also necessary for the acquisition of uterine receptivity. This notion was originally suggested by reports from our and other clinical centers worldwide that IVF patients with repeated implantation failure subjected to endometrial biopsy exhibit a substantial improvement in their chances to conceive. These findings, followed by the demonstration of an elevated pro-inflammatory cytokine/chemokine expression, as well as an increased abundance of immune cells, in the endometrium of these patients, raised the idea that acquisition of uterine receptivity is closely associated with an inflammatory response. This review summarizes the molecular and biochemical evidence that confirm this notion and proposes a mechanism by which injury-induced inflammation improves uterine receptivity and the subsequent pregnancy outcome.

The Role of Endometrial Biopsy in the Evaluation of Recurrent Implantation Failure

2005 ◽  
Vol 84 ◽  
pp. S272
Author(s):  
J.M. Hartnett ◽  
L. Engmann ◽  
M.M. Sanders ◽  
D. Maier ◽  
J. Nulsen ◽  
...  
Keyword(s):  
Endometrial Biopsy ◽  
Implantation Failure ◽  
Recurrent Implantation Failure

scholarly journals MiR-133b Improves Decidualization of Endometrial Stromal Cells by Targeting KLF12 in Recurrent Implantation Failure

2021 ◽  
Author(s):  
Fenglin Mei ◽  
Chengcai Kong ◽  
Yan Wang ◽  
Jing Zhuang ◽  
Pingping Xue ◽  
...  
Keyword(s):  
Western Blot ◽  
Stromal Cells ◽  
Luciferase Reporter ◽  
Implantation Failure ◽  
Reporter System ◽  
Recurrent Implantation Failure ◽  
Endometrial Stromal Cells ◽  
Protein Levels ◽  
Qrt Pcr

Abstract Purpose Impaired decidualization contributes to the infertility in recurrent implantation failure (RIF). Herein, we focused on the function and probable mechanisms of miR-133b in endometrial stromal cells decidualization.Methods miR-133b and KLF12 protein levels in midsecretory endometrial tissues derived from women with and without RIF were measured by qRT-PCR and Western blot. Primary human endometrial stromal cells (HESCs) were isolated and cultured for in vitro decidualization assays. Luciferase reporter, qRT-PCR and Western blot assays were used to measure the relationship between miR-133b and KLF12.Results miR-133b was significantly downregulated, whereas KLF12 was upregulated in endometrial tissues from RIF. miR-133b effectively promoted HESCs in vitro decidualization through the modulation of KLF12 expression and the activation of LIF/STAT3 pathway. Conversely, inhibition of miR-133b expression reversed these effects. In addition, the luciferase reporter system demonstrated that miR-133b directly inhibited the expression of KLF12 by interacting with 3’ untranslated region of KLF12.Conclusion Our data suggest that miR-133b promotes HESCs decidualization by targeting KLF12 and reverses the impaired decidualization in RIF.

P–379 Human platelet lysate improves trophoblast spheroid attachment to primary endometrial epithelial cells from patients with recurrent implantation failure

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
T T T N Nguyen ◽  
Y S S Kwok ◽  
S Russell ◽  
C Librach
Keyword(s):  
Epithelial Cells ◽  
Cell Line ◽  
Fluorescent Microscopy ◽  
Endometrial Receptivity ◽  
Platelet Lysate ◽  
Implantation Failure ◽  
Trophoblast Cells ◽  
Recurrent Implantation Failure ◽  
Endometrial Epithelial Cells

Abstract Study question Could non-autologous platelet lysate (PL) increase attachment of HTR–8 spheroids in vitro to primary endometrial epithelial cells (EECs) from patients with recurrent implantation failure (RIF)? Summary answer Increased quantity of HTR–8 spheroids attached to primary EECs, isolated from patients with RIF, suggests in vitro treatment with non-autologous PL could improve endometrial receptivity. What is known already Inadequate endometrial receptivity and thickness are major causes for RIF. Recent studies suggest that platelet-rich plasma (PRP) may improve pregnancy outcomes for RIF and/or thin endometrium (TE) patients. Our previous results show that a commercially sourced and non-autologous human PRP/PL (HPL) promotes EC proliferation in vitro, suggesting that HPL may help to standardize future clinical treatments. In addition to EC proliferation, HPL treatment may improve embryo attachment to primary EECs isolated from patients with a history of RIF. In vitro attachment assays with trophoblast spheroids (embryo model) could help elucidate the effect of HPL on endometrial receptivity in RIF patients. Study design, size, duration Endometrial tissue was collected from nine RIF patients at the CReATe Fertility Centre, Toronto, Canada (Veritas REB#16580): five with (RIF+TE) and four without a TE (RIF only). Primary EECs were enzymatically isolated and treated with serum-free culture media (SFM) or 1% HPL in SFM for 48 hours before performing the attachment assay. Trophoblast cells (HTR–8/SVneo) were grown in suspension on a rocker to form 70–100 uM spheroids over 24 hours before use in the assay. Participants/materials, setting, methods Spheroids were fluorescently labelled with calcein-AM for 30 minutes and size-selected to capture spheroids similar in size to a human blastocyst. Spheroids were seeded on top of EEC monolayers and calcein fluorescence was immediately measured by a spectrophotometer. Following the 1-hour incubation, unattached spheroids were aspirated, and fluorescence was measured again. Spheroids were also individually quantified by fluorescent microscopy and ImageJ™ software. The percentage of spheroid attachment was calculated for calcein fluorescence and ImageJ™ quantification. Main results and the role of chance The HTR–8/SVneo cell line, derived from human first-trimester extravillous trophoblast cells (EVT), has been shown to be a suitable cell line to assess adhesion and invasion in vitro. Trophoblast spheroids generated from this cell line visually resembled a blastocyst and maintained expression of the EVT and implantation biomarkers: GATA3, ITGA5, and LIF. Primary EECs, treated for 48 hours with SFM supplemented with 1% commercially sourced and non-autologous HPL, overall exhibited increased attachment to HTR–8 spheroids. The percentage of spheroid attachment, as measured by fluorescence alone, significantly increase from 47.98% to 64.27% (P < 0.01) of seeded spheroids in RIF+TE EEC cultures, and from 48.12% to 85.77% (P < 0.001) of seeded spheroids in RIF only EEC cultures. Quantification by fluorescent microscopy and ImageJ™ software for individual calcein-stained spheroids, revealed a significant increase in spheroid attachment, from 57.52% to 86.5% (P < 0.01) in RIF+TE EEC cultures, and from 42.58% to 68.90% (P < 0.01) in RIF only EEC cultures. Limitations, reasons for caution Although there was a positive correlation between calcein fluorescence and spheroid quantity, quantification by fluorescence alone may be unreliable due to the variable numbers of cells in each spheroid. Our data suggest a more precise increase in attachment is detected when quantified by fluorescent microscopy and ImageJ™ software. Wider implications of the findings: We report a method for functional assessment of endometrial receptivity in vitro. HPL appears to promote implantation in RIF patients in a model of embryo attachment. We predict that the observed increase in attachment is due to increased endometrial receptivity gene expression, which will be our next investigative avenue. Trial registration number N/A

Intentional endometrial injury enhances angiogenesis through increased production and activation of MMP-9 by TNF-α and MMP-3 in a mouse model

2021 ◽  
Vol 27 (10) ◽  
Author(s):  
Yi-An Tu ◽  
Chia-Hung Chou ◽  
Po-Kai Yang ◽  
Chia-Tung Shun ◽  
Wen-Fen Wen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mouse Model ◽  
Matrix Metalloproteinase ◽  
Active Form ◽  
Implantation Failure ◽  
Recurrent Implantation Failure ◽  
Endometrial Injury ◽  
Tnf Α ◽  
Endometrial Scratching ◽  
Endometrial Epithelial Cells

Abstract There have been reports of improved pregnancy rates after performing intentional endometrial injuries, also known as endometrial scratching, in patients with recurrent implantation failure. In our previous study on intentional endometrial injury, we found an increased expression of matrix metalloproteinase (MMP)-3 following induced injuries to the mice endometrium. In the current study, we further examine whether the rise in MMP-3 could contribute to increased angiogenesis. Female C57B1/6 mice were obtained at 12 weeks of age, and intentional endometrial injuries were induced mechanically in the left uterine horns. Using the appropriate media, uterine-washes were performed on the injured and uninjured (control) horns of the harvested uteri. The uterine tissues were further processed for tissue lysates, histopathology and immunohistochemistry. The results show that intentional endometrial injuries caused an increase in secreted LPA in the injured horns, which were detected in the uterine-washes. In addition, LPA induced increased production of TNF-α in human endometrial epithelial cells (hEEpCs). Furthermore, TNF-α appeared to induce differential and cell-specific upregulation of the MMPs: MMP-3 was upregulated in the epithelial (hEEpCs), while MMP-9 was upregulated in the endothelial cells (human endometrial endothelial cells; hEEnCs). The upregulation of MMP-3 appeared to be necessary for the activation of MMP-9, whose active form stimulated the formation of vessel-like structure by the hEEnCs. The results of this study suggest that there may be enhanced angiogenesis following intentional endometrial injuries, which is mediated in part by TNF-α-induced and MMP-3-activated MMP-9 production.

scholarly journals Expression and significance of miR-30d-5p and SOCS1 in patients with recurrent implantation failure during implantation window

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yuhao Zhao ◽  
Dongmei He ◽  
Hong Zeng ◽  
Jiefeng Luo ◽  
Shuang Yang ◽  
...  
Keyword(s):  
Endometrial Biopsy ◽  
Endometrial Receptivity ◽  
Leukaemia Inhibitory Factor ◽  
In Vitro Fertilisation ◽  
Control Group ◽  
Implantation Failure ◽  
Recurrent Implantation Failure ◽  
Tissue Samples ◽  
Implantation Window

Abstract Background Poor endometrial receptivity is a major factor that leads to recurrent implantation failure. However, the traditional method cannot accurately evaluate endometrial receptivity. Various studies have indicated that microRNAs (miRNAs) are involved in multiple processes of embryo implantation, but the role of miRNAs in endometrial receptivity in patients with recurrent implantation failure (RIF) remains elusive. In the present study, we investigated the presence of pinopodes and the roles of miR-30d-5p, suppressor of cytokine signalling 1 (SOCS1) and the leukaemia inhibitory factor (LIF) pathway in women with a history of RIF during the implantation window. Methods Endometrial tissue samples were collected between January 2018 to June 2019 from two groups of women who underwent in vitro fertilisation and embryo transfer (IVF-ET) or frozen ET. The RIF group included 20 women who underwent ≥ 3 ETs, including a total of ≥ 4 good-quality embryos, without pregnancy, whereas the control group included 10 women who had given birth at least once in the past year. An endometrial biopsy was performed during the implantation window (LH + 7). The development of pinopodes in the endometrial biopsy samples from all groups was evaluated using scanning electron microscopy (SEM). Quantitative reverse transcription-polymerase chain reaction and western blotting were used to investigate the expression levels of miR-30d-5p, SOCS1, and the LIF pathway. Results The presence of developed pinopodes decreased in patients with RIF on LH + 7. The expression level of miR-30d-5p decreased in the endometria during the implantation window of patients with RIF, whereas the mRNA and protein levels of SOCS1 were significantly higher in the RIF group than in the control group. Furthermore, a negative correlation was observed between the expression of miR-30d-5p and SOCS1 (r2 = 0.8362). In addition, a significant decrease in LIF and p-STAT3 expression was observed during the implantation window in patients with RIF. Conclusions MiR-30d-5p and SOCS1 may be potential biomarkers for endometrial receptivity. Changes in pinopode development and abnormal expression of miR-30d-5p, SOCS1 and LIF pathway in the endometrium could be the reasons for implantation failure.

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